Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes
Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes
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DOI：
10.1172/jci2680
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发表时间：
1998-12-15
影响因子：
15.9
通讯作者：
Lee, TH
中科院分区：
文献类型：
--
作者：
Lane, SJ;Adcock, IM;Lee, TH
来自皮质类固醇抵抗（CR）而非皮质类固醇敏感（CS）哮喘患者的未经刺激的外周血单个核细胞（PBMC）表现出活化肽-1（AP-1）-DNA结合增加和糖皮质激素受体（GR）-DNA结合减少。我们测试这些异常是否与AP-1的诱导成分c-fos的过度产生有关。对CS、CR和非哮喘受试者的PBMCs、T细胞和单核细胞中的c-fos转录率、mRNA和蛋白水平以及GR-DNA结合进行定量。与CS患者相比，CR患者的PBMC中基线c-fos转录率、mRNA表达和蛋白水平分别增加了1.7倍、4.2倍和2.3倍。在最佳刺激PMA，有一个5.7-，3.4-和2倍的增加c-fos转录率，mRNA的积累，和蛋白质水平，分别在CR相比，CS PBMC。在T细胞和单核细胞亚群中都检测到这些异常。PMA刺激可使CR患者的PBMC从CS表型转变为CR表型，并与c-Fos和GR之间的直接相互作用有关。用c-fos反义寡核苷酸预处理CR患者的PBMC可增强地塞米松刺激的CR PBMC的GR-DNA结合活性。我们认为，c-fos合成增加是CR哮喘中AP-1结合增加和GR-DNA结合减少的主要机制。
Unstimulated peripheral blood mononuclear cells (PBMCs) from corticosteroid-resistant (CR) but not corticosteroid-sensitive (CS) asthmatics demonstrate increased activating peptide-1 (AP-1)- and decreased glucocorticoid receptor (GR)-DNA binding, We test whether these abnormalities are associated with excessive generation of c-fos, the inducible component of AP-1., The c-fos transcription rate, mRNA and protein levels, and GR-DNA binding were quantitated in PBMCs, T cells, and monocytes from CS, CR, and nonasthmatic subjects. There was a 1.7-, 4.2-, and 2.3-fold greater increase in the baseline c-fos transcription rate, mRNA expression, and protein levels, respectively, in PBMCs derived from CR compared with CS patients. At optimal stimulation with PMA, there was a 5.7-, 3.4-, and 2-fold greater increase in the c-fos transcription rate, mRNA accumulation, and protein levels, respectively, in CR compared with CS PBMCs. These abnormalities were detected in both the T cell and monocyte subpopulations. PMA stimulation converted PBMCs from a CS to a CR phenotype and was associated with direct interaction between c-Fos and the GR, Pretreatment of PBMCs from CR patients with c-fos antisense oligonucleotides enhanced GR-DNA binding activity in CR PBMCs stimulated with dexamethasone, We suggest that increased c-fos synthesis provides a major mechanism for the increased AP-1- and decreased GR-DNA binding seen in CR asthma.